ABSTRACT Activation of immune pathways and networks constitutes an important emerging component of Alzheimer's disease (AD) pathology that presents new opportunities for therapeutic discovery. The overall goal of the study is to define high-quality immune activation networks for AD and to identify novel therapeutic opportunities against these networks using computational drug repurposing. We propose three distinct but complementary aims that leverage recent insights into the genetics, functional genomics, and network biology of immune factors in AD along with computational drug repurposing. First, we will define microglia-associated networks and use these as input to computational drug repurposing methods to identify novel therapeutic opportunities. We will also focus viral perturbations as an environmental source of immune activation in AD. We will build from our preliminary data that shows the influence of specific viral species in networks constructed from multi- omic measures of post-mortem brain tissues. We will then use these virally-modulated AD networks as input to computational drug repurposing to identify novel therapeutic opportunities. Finally, we will evaluate the temporal dynamics of immune activation in AD. AD is a disease of aging that manifests over a period and we hypothesize that role of immune activation in AD is likely to vary along stages of disease. We will study microglial and multi-omic networks in mice lacking each of the specified microglial genes at ages 4, 8, 12, and 24 months characterize the molecular, cellular, and histological effects of immune network activation in AD animal models across animal age and disease stage. The expected outcome of this study is to identify and evaluate drugs that could be repurposed to modulate immune networks towards non-disease states and to potentially identify the most relevant or optimal states or stages of disease for evaluating therapeutic agents targeting immune activation pathways in AD.